The present invention is in the area of biochemistry, and is in particular a method of preparation of 2',3'-dideoxy and 2',3'-dideoxydidehydro nucleosides.
Since 3'-azido-3'-deoxythymidine (FIG. 1, Compound 1) (AZT, Zidovudine, Retrovir) was identified by Mitsuya et al. as a potent antiviral agent against human immunodeficiency virus type 1 (HIV-1), alternatively called human T-lymphotropic virus type III (HTLV-III), a number of other nucleosides have been found to inhibit HIV-1 in vitro.
In particular, a number of 2',3'-dideoxy and 2',3'-didehydrodideoxy nucleosides have been shown to have potent anti-HIV-1 activity. Examples of 2',3'-dideoxy nucleosides which exhibit antiviral activity include 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyadenosine (DDA), 3'-azido-2',3'-dideoxyuridine (CS-87), 2',3'-dideoxyuridine, 2',3'-dideoxyinosine, 2',3'-dideoxyguanosine, 3'-azido -methyl-2',3'-dideoxycytidine (CS-92), and 3'-azido-2',3'-dideoxyuridine (CS-85). Examples of 2',3'-didehydrodideoxy nucleosides (2',3'-unsaturated nucleosides) with antiviral activity include 2',3'-didehydrodideoxycytidine, 2',3'-didehydrodideoxyuridine, 2',3'-didehydrodideoxyadenosine, 2',3'-dideoxydidehydroinosine, and 2',3'-dideoxydidehydroguanosine.
In view of the importance of 2',3'-dideoxynucleosides and 2',3'-dideoxydidehydro nucleosides, it is desirable to have a facile, efficient and general route of synthesis to these compounds. While several methods exist for the synthesis of 2',3'-dideoxynucleosides and 2',3'-didehydrodideoxy nucleosides, none has the ability to produce both types of nucleosides in an easy procedure which is applicable to both purine and pyrimidine nucleosides.
The first reported method to produce 2',3'-didehydrodideoxy nucleosides involved the base promoted elimination of 3'-O-sulfonyl esters of 2'-deoxyynucleosides. However, the synthetic route is limited to pyrimidines and cannot be used for purines. Horowitz, J. P., ea al., J. Org. Chem. 31, 205 (1966); Horowitz, J. P. et al., J. Org. Chem. 32, 817 (1967); and Horowitz, et al., J. Am. Chem. Soc. 86, 1896 (1964).
In recent years, some 2',3'-dideoxydidehydro nucleosides have been obtained directly from the corresponding ribonucleosides through their reaction with acetoxyisobutyryl halides, followed by the reductive elimination of the 2'(3')-acetoxy-3'(2')-halogeno derivatives with chromous ion. U.S. Pat. No. 3,817,982 (1974); Chem. Abstr. 81, 63942 (1974); Russell, A. F., et al., J. Am. Chem. Soc. 95, 4025 (1973); Jain, T. C., et al., J. Org. Chem. 39, 30 (1974); Classon, B., et al., Acta Chem. Scand. Sect B 32, 251 (1982); Robins, M. J., et al., Tetrahedron Letters 25, 367 (1984). In a variation of this method, zinc in dimethylformamide can be used instead of chromous acetate. Robbins, M. et al., Tet. Letters 25, 367 (1984). Though this method has been effective for the preparation of 2',3'-didehydrodideoxyadenosine and uridine, its applicability for the synthesis other unsaturated nucleosides such as inosine and guanosine has been very poor. Jain, et al., J. Org. Chem. 39, 20 (1974). Further, the reaction is difficult, and results in several products, and is therefore an inefficient route to obtain the 2',3'-unsaturated compounds.
2',3'-Dideoxynucleosides have been obtained through the Barton deoxygenation of dithiocarbonates or thionocarbonates of 2'-deoxynucleosides in 40-55% yield. Prisbe, E. J., and Martin, J. C., Synth. Commun. 15, 401 (1985); Webb, R. R., et al., Nucleosides Nucleotides 7, 147 (1988). However, the Barton scheme does not provide a route to 2',3'-didehydrodideoxynucleosides.
Therefore, it is an object of the present invention to provide a general synthetic method for both 2',3'-dideoxy and 2',3'-didehydrodideoxy nucleosides from the corresponding ribonucleosides.
It is another object of the present invention to provide a method for the synthesis of 2',3'-dideoxy and 2',3'-dideoxydidehydro nucleosides which is facile and efficient.
It is a further object of the present invention to provide a method of synthesis of 2',3'-dideoxy and 2',3'-dideoxydidehydro nucleosides which is applicable to both purine and pyrimidine nucleosides.